The technical field of this invention is the treatment of neurological diseases and, in particular, the treatment of neurotransmitter-deficiency diseases.
Neurotransmitters are small molecules (less than 1000 daltons molecular weight) which act as chemical means of communication between neurons. They are synthesized by the presynaptic neuron and released into the synaptic space where they are then taken up by postsynaptic neurons.
Neurotransmitter deficits have been implicated in various neurological diseases. Lack of neurotransmitter-mediated synaptic contact causes neuropathological symptoms, and can also lead to the ultimate destruction of the neurons involved. However, it has been discovered that localized delivery of the relevant neurotransmitter to the target tissue may reverse the symptoms without the need for specific synaptic contact.
For example, paralysis agitans, more commonly known as Parkinson's disease, is characterized by a lack of the neurotransmitter, dopamine within the striatum of the brain, secondary to the destruction of the dopamine secreting cells of the substantia nigra. Affected subjects demonstrate a stooped posture, stiffness and slowness of movement, and rhythmic tremor of limbs, with dimentia being often encountered in very advanced stages of the disease. These clinical symptoms can be improved by the systemic administration of dopamine precursors, such as levodopa (L-dopa)(Calne et al., (1969) Lancet ii:973-976) which are able to cross the blood-brain barrier, and to be converted into dopamine in the brain, or agonists, such as bromocriptine (Calne et al., (1974) Bri. Med. J. 4:442-444). Dopamine, itself, cannot be administered systemically because of its inability to cross the blood-brain barrier.
However, one of the drawbacks of this type of chemical therapy is that other neurological structures using dopamine as a neurotransmitter are affected. In addition, it becomes difficult to administer the correct drug dosage with time because the "therapeutic window" narrows (i.e., just after administration, the patient is overdosed, exhibiting excessive spontaneous movement; some time therafter the drug level may become insufficient, causing the patient to again express parkinsonian symptoms). Therefore, what is needed is a method of continuous or constitutive delivery of a required neurotransmitter to a localized target region which is deficient in that neurotransmitter.
Recently, remedial transplantation of neurotransmitter-secreting tissue has been accomplished using the patient's own tissue so as not to elicit an immune response. For example, dopamine-secreting tissue from the adrenal medulla of Patients suffering from Parkinson's disease has been implanted in their striatum with reasonable success. However, this procedure is only used in patients less than 60 years of age, as the adrenal gland of older patients may not contain sufficient dopamine-secreting cells. This restriction limits the usefulness of this procedure as a remedy since the disease often affects older people.
Furthermore, brain surgery involves a substantial risk of morbidity, and abdominal surgery performed to excise portions of the adrenal gland Poses substantial risks as well. Moreover, it is not actually known whether it is the implanted cells actually producing dopamine, or the trauma of the surgery, itself, which alleviates the clinical symptoms. In fact, stereotaxic surgery, or the placement of precisely localized lesions in the brain has been practiced in younger, less affected patients to relieve parkinsonian symptoms. The procedure is risky, however, and opinions among neurosurgeons still differ as to the best way of making the lesion and what its ideal location should be.
Alternatives have been the transplantation of either allograft (identical tissue from another of the same species), or xenograft (similar tissue from another of a different species) dopamine-secreting tissue. However, recent studies have shown that although the brain is considered "immuno-priviledged", rejection ultimately occurs with both allo- and xenografts. This problem necessitates the co-adminstration of immunosuppressors, the use of which renders their own set of complications and deleterious side-effects.
Therefore, there exists a need for improved therapies for neurotransmitter-deficiency diseases in general, and in particular, a need for systems which can augment or replace the functions of dysfunctional neurotransmitter-producing areas of the brain without causing excessive trauma. More specifically, there exists a need for a method of providing a neurotransmitter to a localized region of the nervous system of a subject deficient in this hormone, the correct dosage of which will be continually or constitutively delivered over time.
Accordingly, it is an object of the present invention to provide a method for delivering a neurotransmitter to a subject deficient in that neurotransmitter, and to provide a method of delivering a neurotransmitter to a localized target region of the nervous system of a subject. It is another object of the present invention to provide a method of delivering a neurotransmitter to a subject in a constitutive manner, and to provide an implantable device which is capable of constitutively delivering a neurotransmitter to a localized region of the nervous system of a subject deficient in that neurotransmitter.
Yet another object is to provide an implantable cell culture device which is retrievable, and whose contents are renewable with new and/or additional neurotransmitter-secreting cells.
A further object is to provide a cell culture device which protects the cells therein from an immunological response or from viral infection, while allowing the delivery of a neurotransmitter therefrom.